Newly synthesized piperazine derivatives as tyrosinase inhibitors: in vitro and in silico studies

Dokuzparmak, Cigdem; Tuncay, Fulya Oz; Ozdemir, Serap Basoglu; Kurnaz, Busra; Demir, Ilke; Çolak, Ahmėt; Erdem, Safiye Sağ; Yıldırım, Nuri

doi:10.1007/s13738-021-02487-3

Cited by 3 publications

(1 citation statement)

References 47 publications

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“…However, they are characterized by inherent drawbacks such as high water solubility, poor penetration, and inadequate stability, which can potentially result in adverse reactions like skin irritation, allergies, and toxicity. − As a result, researchers have been striving to identify safer and more effective TYR inhibitors. Currently, the piperazine group, due to its basicity, flexibility, potential hydrophobic interactions, and broad pharmacological activity, has emerged as a critical component in the design of structurally innovative and highly efficacious TYR inhibitors. − …”

Section: Introductionmentioning

confidence: 99%

Artificial Intelligence-Assisted Optimization of Antipigmentation Tyrosinase Inhibitors: De Novo Molecular Generation Based on a Low Activity Lead Compound

Cai,

Chen,

Jiang

et al. 2024

J. Med. Chem.

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Artificial intelligence (AI) de novo molecular generation is a highly promising strategy in the drug discovery, with deep reinforcement learning (RL) models emerging as powerful tools. This study introduces a fragment-by-fragment growth RL forward molecular generation and optimization strategy based on a low activity lead compound. This process integrates fragment growth-based reaction templates, while target docking and drug-likeness prediction were simultaneously performed. This comprehensive approach considers molecular similarity, internal diversity, synthesizability, and effectiveness, thereby enhancing the quality and efficiency of molecular generation. Finally, a series of tyrosinase inhibitors were generated and synthesized. Most compounds exhibited more improved activity than lead, with an optimal candidate compound surpassing the effects of kojic acid and demonstrating significant antipigmentation activity in a zebrafish model. Furthermore, metabolic stability studies indicated susceptibility to hepatic metabolism. The proposed AI structural optimization strategies will play a promising role in accelerating the drug discovery and improving traditional efficiency.

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Section: Introductionmentioning

confidence: 99%

Artificial Intelligence-Assisted Optimization of Antipigmentation Tyrosinase Inhibitors: De Novo Molecular Generation Based on a Low Activity Lead Compound

Cai,

Chen,

Jiang

et al. 2024

J. Med. Chem.

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A QSAR study to predict the survival motor neuron promoter activity of candidate diaminoquinazoline derivatives for the potential treatment of spinal muscular atrophy

Gurses

Erdem

Saçan

2023

SAR and QSAR in Environmental Research

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Synthesis, molecular modeling, quantum chemical calculations and in silico drug profiling of the novel (4-phenylpiperazin-1-ium) hydrogenfumarate as a tyrosinase inhibitor

Jemai,

Issaoui,

Roisnel

et al. 2023

Zeitschrift Für Physikalische Chemie

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The complexation between fumaric acid (FA) and 1-phenylpiperazine (1 PP) is a fruitful cooperation that allowed the preparation of a new organic crystal entitled (4-phenylpiperazin-1-ium) hydrogenfumarate denoted by 4PPHFUM, which is reported in the present manuscript. This new substance is created by the slow evaporation that occurs when 1-phenylpiperazine and fumaric acid are combined in a stoichiometric 1:1 ratio. The stacking of the crystal is provided by O–H⋯O, N–H⋯O and C–H⋯O hydrogen bonds, also supported by C–H⋯π interactions between the organic cations. The importance of these interactions in the formation of this new crystal is confirmed by the Hirshfeld surface analysis which showed that H-bonds and supramolecular C–H⋯π interactions account for about half of the non-covalent interactions existing in this compound. These non-covalent bonds that encompass the synthesis and design of this supramolecule have also been analyzed in detail using a quantum chemical computational study. Using the docking – based drug design strategy, we investigated the therapeutic effect of this cooperative outcome between fumaric acid and 1-phenylpiperazine to demonstrate the improved therapeutic property of this novel non-covalent compound as a tyrosinase inhibitor. 4PPHFUM was found to be a potent tyrosinase inhibitor with high interaction energy with its protein, higher than that of the most potent tyrosinase inhibitors (thiamidol, hydroquinone, resorcinol, hexylresorcinol and kojic acid).

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Newly synthesized piperazine derivatives as tyrosinase inhibitors: in vitro and in silico studies

Cited by 3 publications

References 47 publications

Artificial Intelligence-Assisted Optimization of Antipigmentation Tyrosinase Inhibitors: De Novo Molecular Generation Based on a Low Activity Lead Compound

Artificial Intelligence-Assisted Optimization of Antipigmentation Tyrosinase Inhibitors: De Novo Molecular Generation Based on a Low Activity Lead Compound

A QSAR study to predict the survival motor neuron promoter activity of candidate diaminoquinazoline derivatives for the potential treatment of spinal muscular atrophy

Synthesis, molecular modeling, quantum chemical calculations and in silico drug profiling of the novel (4-phenylpiperazin-1-ium) hydrogenfumarate as a tyrosinase inhibitor

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